The present invention relates to a process for the preparation of N-[heteroaryl]hydroxyalkylamines, novel N-[heteroaryl]hydroxyamines obtainable by the process and processes for preparing piperazine derivatives using the N-[heteroaryl]hydroxyalkylamines.
GB 2 255 337A discloses piperazine derivatives having the general formula I 
and their pharmaceutically acceptable acid addition salts as 5-HT1A binding agents, particularly 5-HT1A antagonists and, in particular, their use in the treatment of CNS disorders, for example, anxiolytics. They may also be used as anti-depressants, hypertensives and as agents for regulating the sleep/wake cycle, feeding behaviour and/or sexual function.
In formula I above A is C2-4 alkylene optionally substituted by one or more lower alkyl groups, Z is oxygen or sulphur, R is hydrogen or lower alkyl, R1 is an optionally substituted monocyclic or bicyclic aryl or heteroaryl radical, R2 represents an optionally substituted monocyclic or bicyclic heteroaryl and R3 represents inter alia hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl (lower) alkyl, aryl, aryl (lower) alkyl and heteroaryl (lower) alkyl.
GB 2 255 337A also discloses piperazine derivatives having the general formula II 
where R, R1, R2 and A are as defined above as chemical intermediates for the preparation of the piperazine derivatives having the general formula I. The chemical intermediates are reacted with an acid having the formula R3xe2x80x94CZxe2x80x94OH where R3 and Z are as defined above or a reactive derivative of such an acid to prepare the compounds having formula I. The chemical intermediates were prepared by the following process: 
(where R, R1, R2 and A are as defined above, Hal is halo, particularly chloro or bromo and Axe2x80x2 is an alkylene chain of 1 to 3 carbon atoms optionally substituted by one or more lower alkyl groups)
The reduction may be carried out with, for example, a boron reducing agent eg boranedimethyl sulphide or a complex metal hydride, e.g. lithium aluminium hydride.
The present invention is based upon the discovery that the aforesaid chemical intermediates having formula II can be prepared by means of a process involving a novel rearrangement reaction. The rearrangement reaction has the advantages that it can be performed in high yields and that it can be carried out as an asymmetric synthesis for the preparation of particular stereosomeric forms.
The present invention provides novel compounds having formula V
R5Oxe2x80x94Axe2x80x94NR4xe2x80x94R2xe2x80x83xe2x80x83(V)
and the salts thereof in which A is as defined above; R2 represents a group having the formula R6xe2x80x94Nxe2x95x90CR7xe2x80x94 where R6 and R7, together with carbon atom and nitrogen atom to which they are attached, complete an optionally substituted monocyclic or bicyclic heteroaryl radical and R4 and R5 each represent a hydrogen atom or together represent xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94. Thus the compounds having formula V include the compounds having formula Va
HOxe2x80x94Axe2x80x94NHxe2x80x94R2xe2x80x83xe2x80x83(Va)
and compounds having formula Vb 
and compounds having the formula Vc 
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic radical containing one or more hetero atoms (eg oxygen, nitrogen, sulphur) and which may be optionally substituted by one or more substituents. Examples of such substituents include lower alkyl (for example, methyl, ethyl and propyl), lower alkoxy (for example, methoxy and ethoxy), halogen, trifluoromethyl, nitro, cyano, di(lower alkyl)amino and (lower) alkoxycarbonyl. The heteroaryl radical may, for example, contain up to 10 ring atoms. Preferably the heteroaryl radical is a monocyclic radical containing 5 to 7 ring atoms. The hetero ring of R2 must contain a nitrogen hetero atom and may also contain one or more further hetero atoms.
When R2 is a bicyclic heteroaryl radical both rings of the radical may contain hetero ring atoms or only one ring may contain a hetero atom or atoms. In the latter instance the radical R2 is connected to the rest of the molecule of formula (I) via the ring containing the hetero atom(s).
Examples of the heteroaryl radical R2 include monocyclic radicals containing one hetero atom, eg optionally substituted 2-pyridyl, particularly 2-pyridyl, monocyclic radicals containing two hetero atoms, eg 2- or 4-thiazolyl (particularly 2-thiazoyl) and bicyclic radicals containing one or two hetero atoms eg 2-quinolinyl or 1- or 3-isoquinolinyl (particularly 2-quinolinyl).
The term xe2x80x9clowerxe2x80x9d as appplied to alkyl and alkoxy groups herein means that the alkyl or alkoxy group contains 1 to 6 carbon atoms preferably 1 to 4 carbon atoms. The term xe2x80x9c(lower)xe2x80x9d alkoxy carbonylxe2x80x9d means alkoxycarbonyl in which the alkoxy group is xe2x80x9clowerxe2x80x9d. Examples of lower alkyl include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, isopentyl and hexyl.
The group A may represent dimethylene, trimethylene, tetramethylene or a lower alkyl-substitution product thereof, for instance, xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94. Where one or more lower alkyl substituents are present, the group A may contain an asymetric carbon atom. Thus the new compounds having formula V may exists in different steroisomeric forms. Different stereoisomers are preferably prepared by using a starting material of formula VII (see below) in a particular stereoisomeric form.
The invention provides a process for the preparation of a compound having formula Va
HOxe2x80x94Axe2x80x94NHxe2x80x94R2xe2x80x83xe2x80x83(Va)
or a salt thereof where R2 and A are as defined above, which comprises subjecting a compound having the formula VI
R2Oxe2x80x94Axe2x80x94NH2xe2x80x83xe2x80x83(V)
where R2 and A are as defined above, to rearrangement. The rearrangement can be carried out by heating the compound having formula VI in the presence of a suitable solvent, optionally in the presence of an acidic catalyst. The rearrangement reaction has the advantage that it can be carried out in very high yields.
The compounds having the formula VI can be prepared by ether formation in known manner from alcohols having the formula VII
HOxe2x80x94Axe2x80x94NH2xe2x80x83xe2x80x83(VII)
where A is as defined above. In particular the alcohol may be converted into an alkali metal salt thereof, particularly the sodium, potassium or lithium salt, in solution in a suitable solvent prior to reaction with a compound having the formula R2xe2x80x94X where X is a leaving group, preferably, chloro, bromo or fluoro. The salt formation is preferably carried out by treating the alcohol (VII) with potassium t-butoxide in tetrahydrofuran to form the potassium salt of the alcohol.
The aminoalcohols having formula Va are useful for the preparation of alkylating agents for the introduction of a substituted alkyl group having the formula X
xe2x80x94Axe2x80x94NHxe2x80x94R2xe2x80x83xe2x80x83(X)
Such alkylating agents are reacted with a piperazine derivative having the formula IIIa 
where R1 is as defined above to form the aforesaid chemical intermediates having formula II which in turn can be used to prepare the pharmaceutically useful piperazine derivatives having formula I.
We have found that conventional alkylating agents, namely, those of the formula RY where R is the alkyl or substituted alkyl group and Y is a leaving group such as a chlorine or bromine atom or tosyloxy group, are not generally suitable for use in the aforeside reaction with the piperazine derivative having formula IIa to prepare the compund having formula II. However, we have surprisingly found that the reaction is possible by using a compound having the formula Vb or Vc, preferably Vc as reactant. The compounds having the formulae Vb and Vc may be prepared by a process which comprises reacting a compound having the formula Va with a compund having the formula SOnX2 where n is 1 or 2 and X is a leaving group. X may be halogen particularly chlorine or a residue from imidazole. When n is 1 then the product of the process is of formula Vb. When n is 2 the product of the proces is of formula Vc. The compounds having formula Vc may also be prepared by oxidation of a compound having formula Vb. The oxidation may be carried out according to known methods.
The invention also includes a process for the preparation of a compound having the formula III or a salt thereof which comprises reaction of a compound having formula IIIa or a salt thereof with a compound having formula Vb or Vc, preferably a compound having formula Vc. The reaction may be followed by reaction with a compound having the formula HOCZR3 or a reactive dervative thereof in the preparation of compound of formula I or salt thereof.
The following reaction scheme illustrates a synthetic route according to the invention where Ar represents aryl, preferably substituted or unsubstituted phenyl, for example 2-methoxyphenyl: 
The chirality of the product of the reaction of the compound having formula Vb or Vc with the compound having formula IIIa at position 5 of the [1,2,3]oxathiazolidine ring is inverted during the reaction. The chirality at position 4 of the said ring is retained during the reaction.